Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome

Abstract

Late-onset Alzheimer's disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.

Serum Metabolites Associated with Brain Amyloid Beta Deposition, Cognitive Dysfunction, and Alzheimer’s Disease Progression

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Gut Microbiome Alterations Precede Cerebral Amyloidosis and Microglial Pathology in a Mouse Model of Alzheimer’s Disease

“…In humans, the prevalence of AD or other dementias is 11% in males and 16% in females at the age of 71 and older, respectively [81]. This discrepancy might be due to the longer life-span of women or related health factors as well as interactions between genetic factors and sex hormones [82][83][84]. However, the causes of the observed discrepancy remain unclear.…”

Partial inhibition of mitochondrial complex I attenuates neurodegeneration and restores energy homeostasis and synaptic function in a symptomatic Alzheimer’s mouse model

“…The consistent failure of clinical trials focused on reducing Aβ levels and aggregation suggests that such therapies may not work in AD patients regardless of disease stage, underscoring the need to discover novel targets and therapies for AD 1,2 . Recent studies demonstrated that altered energy homeostasis associated with reduced cerebral glucose uptake and utilization, altered mitochondrial function and microglia and astrocyte activation might underlie neuronal dysfunction in AD [3][4][5][6][7] . Intriguingly, accumulating evidence suggests that non-pharmacological approaches, such as diet and exercise, reduce major AD hallmarks by engaging an adaptive stress response that leads to improved metabolic state, reduced oxidative stress and inflammation, and improved proteostasis 8 .…”